Aryl amines with benzylic substituents (i.e., α-branched aryl amines, e.g., 1, Scheme 1) are widely used building blocks for the synthesis of pharmaceuticals, agrochemicals, pesticides, chiral auxiliaries, and chiral ligands. New methods are needed for the preparation of α-branched aryl amines. Specifically, there is a need for methodology that prepares chiral α-branched aryl amines under mild and/or catalytic conditions. Amines with α-aryl substituents can be readily prepared from α-branched aryl phthalimides (cf., 2) by hydrazinolysis. The precursor α-branched aryl phthalimide functional group comprises many pharmaceuticals, agrochemicals, and pesticides.

The Mannich and Ugi reactions are the oldest and most widely used methods for preparing complex amines (cf. Scheme 2, panels A and B). Under each of these conditions, an amine condenses with a ketone or aldehyde to form an imine or iminium ion (cf. 3) intermediate. Under the Mannich reaction conditions, this intermediate subsequently reacts with an enolizable ketone, aldehyde, or preformed enolate to give a β-amino carbonyl. Under the Ugi (multicomponent) reaction conditions, an imine reacts with an isocyanide, and the resulting intermediate is subsequently trapped by, for example, water to give an α-amino amide. In the Petasis modification of the Mannich reaction, vinyl and aryl boronic acids are treated with a mixture of amine and carbonyl to give vinyl amines and aryl amines, respectively. A major practical advantage of these reactions includes the opportunity to exploit the multicomponent facets of these processes for the single-step preparation of complex amines.

As demonstrated by the previous examples, iminium ions are the most fundamental reactive intermediates for processes that prepare amine-containing organic molecules. Iminium intermediates are highly electrophilic at carbon and are known to react with a myriad of nucleophiles to give products with complex and diverse structures. Methods have recently emerged for generating iminium ions from N,O-acetals (cf. 4, Scheme 3) in the presence of Lewis acids (for examples, see Renaud, P., Stojanovic, A. Tetrahedron Letters 1996, 37, 2569-2572, Stojanovic, A., Renaud, P., Schenk, K. Helvetica Chimica Acta 1998, 81, 268-284, Liu, R.-C., Huang, W., Ma, J.-Y., Wei, B.-G., Lin, G.-Q. Tetrahedron Letters 2009, 50, 4046-4049, Onomura, O., Ikeda, T., Kuriyama, M., Matsumura, Y., Kamogawa, S. Heterocycles 2010, 82, 325-332, Lee, W.-I., Jung, J.-W., Jang, J., Yun, H., Suh, Y.-G. Tetrahedron Letters 2013, 54, 5167-5171). Under these conditions, the Lewis acid reagent likely activates the N,O-acetal by coordinating to oxygen (cf. 5). Elimination of the Lewis acid-coordinated oxygen atom forms an iminium ion (cf. 6), which is poised to react intermolecularly with a nucleophile to form the amine product (cf. 7).

Despite the advances in the synthesis of complex nitrogen-containing organic molecules via the Mannich and Ugi reactions, alternative procedures that avoid the use of primary amines, boronic acids, and isocyanides would be beneficial when the desired molecules contain sensitive functional groups. In this regard, N,O-acetals are promising alternatives for the generation of iminium ion intermediates. Due to their potential utility, there is a need for improved methods for preparing N,O-acetals that are both more efficient and can give rise to a library of substrates. Additionally, the scope of nucleophiles that are capable of reacting with the putative iminium ion intermediates has not been fully explored.